Novel phenothiazines

ABSTRACT

Novel phenothiazines of the formula   WHEREIN X is selected from the group consisting of hydrogen, chlorine, trifluoromethyl, methylthio and methoxy, B is selected from the group consisting of hydrogen and alkyl of 1 to 3 carbon atoms, p is 0 or 1, R is selected from the group consisting of hydrogen and alkoxy of 1 to 3 carbon atoms and R1 and R2 are individually selected from the group consisting of hydrogen and alkyl of 1 to 3 carbon atoms and their non-toxic, pharmaceutically acceptable acid addition salts having neuroleptic activity and frequently antihistaminic activity and their preparation.

United States Patent 1 Derible et al.

[ Dec.2, 1975 NOVEL PHENOTHIAZINES [75] Inventors: Pierre Henri Derible,Le Perreux;

Jean-Paul Lavaux, Paris; Jacques Laurent, ChiIly-Mazarin, all of [21]Appl. No.: 539,639

[30] Foreign Application Priority Data Jan. 21, 1974 France 74.01880[52] US. Cl 260/243 A; 424/247; 260/2936]; 260/296 B [51] Int. Cl. C07D209/14 [58] Field of Search 260/243 A [56] References Cited UNITEDSTATES PATENTS 3,873,534 3/1975 Soudijn et al 260/243 A FOREIGN PATENTSOR APPLICATIONS 41-19806 11/1966 Japan 260/243A OTHER PUBLICATIONSChemical Abstracts, Vol. 57, Cols. 16531 to 16532 (1963).

Primary Examiner-John D. Randolph Attorney, Agent, or FirmHammond &Littell [57] ABSTRACT Novel phenothiazines of the formula l X C cn -in-(CH2 H R wherein X is selected from the group consisting of hydrogen,chlorine, trifluoromethyl, methylthio and methoxy, B is selected fromthe group consisting of hydrogen and alkyl of 1 to 3 carbon atoms, p is0 or 1, R is selected from the group consisting of hydrogen and alkoxyof 1 to 3 carbon atoms and R and R are individually selected from thegroup consisting of hydrogen and alkyl of l to 3 carbon atoms and theirnontoxic, pharmaceutically acceptable acid addition salts havingneuroleptic activity and frequently antihistaminic activity and theirpreparation.

11 Claims, No Drawings NOVEL PHENOTI-IIAZINES other preferred group ofcompounds,-X is trifluoromethyl, B and R are hydrogen and p is l.

Among the preferred compounds of the invention are STATE OF THE A TCommonly assigned U.S. patent application Ser. No.

407,995 filed Oct. 19, 1973 discloses lO-(piperidinoal- 5 piperidine andits hydrochloride; 4-(3-indolyl)-l-[ykyl) phenothiazines which aresubstituted in the 4-posi-(2"-trifluoromethyl-l0"-phenothiazinyl)-propyl]- tion of the piperidinogroup with a substituted alkoxy piperidine and its hydrochloride;4-(6'-methoxy-2- group which possess ncuroleptic, analgesic,spasmomethyl-3-ind0lyl)-l-['y-(2"-trifluoromethyl-l0"- lytic andantihistaminic activity., phenothiazinyl)-propyl]-piperidine and itshydrochlov ride; and 4-(3-indolyl)-I-[B-methyl-y-(2"-tri- OBJECTS THEINVENTION v fluoromethyl-l0"-phenothiazinyl)-propyl]-piperidine v I vand its hydrochloride. 7 It is an object of the invention to provide thenovel Examples of Suilable acids for the "On-toxic, P

h hi i f f r l 1 d h i nomtoxic, Pharl ceutically acceptable acidaddition salts are inorganic maceutically acceptable acid addition saltsand a novel aclds Such as hydrochloric acid hydrobromlc acld, yprocess ftheir preparation droiodic acid, nitric acid, sulfuric acid andphosphoric It is another object of the invention to provide novel andorganic acids such as acetlc acid mimic i neuroleptic compositionsbenzoic acid, maleic acid, fumaric acid, succmic acid, It is a furtherob.ect the invenfon t tartaric acid, citric'acid, oxalic acid, glyoxylicacid, as- J 1 prov e a partic acid, alkylsulfonic acids and arylsulfonicacids.

Si 2 i f inducing neuroleptic activity in Warm The novel process of theinvention for the prepara- 00 e amma tion of the phenothiazines offormula I comprises react- These and other objects and advantages of theinveni g a compound of the formula tion will become obvious from thefollowing detailed description.

II THE INVENTION X The novel phenothiazines of the invention are se- Llected from the group consisting of compounds of the 2 2 p formula B C-CH- C V, v l J wherein X is selected from the group consisting ofhywherein X, B and p have the above definitionsand Y is drogen,chlorine, trifluoromethyl, methylthio and mechlorine or bromine with anindole derivative of the thoxy, B is selected from'thegroup consistingof hydroformula l R III gen and alkyl of l to 3 carbon atoms, p is 0 orI, Ris wherein R, R and R have the above definitions to selected fromthe group consisting of hydrogen and alkform the corresponding compoundwhich can then be oxy of l to 3 carbon atoms and R and R are individu- 5reacted with an acid to form the acid addition salt. any selected fromthe l of hydrqgenznd In a preferred embodiment, the reaction is effectedin alkyl 1 to 3 carbon atoms and h non'toxlc p an inert organic solventsuch as amyl alcohol or methyl macuurcauy acceptable acld addmon saltsethyl ketone in the presence of an alkaline agent such In the allkyl toas sodium carbonate, potassium carbonate Ul triethylatoms may be methylprqpy or 1 9 or amine to act as acid acceptor for the acid formed in theexample and thealkoxy of-l .to 3 .carbon atoms could reaction t bemethoxy or ethoxyfor example.

Among preferred.substituents offormula I, X is tri- In a variant of theprocess of the invention, a comfluoromethy-LB is hydrogen or methyl andpis '1. In an- Pou d of the formula either reducing the compound withgaseous hydrogen in the presence of a palladium based catalyst to form awherein X and B have the above definition 1 is reacted compound offormula Ill in which R is hydrogen or rean mdole of the formula acting acompound of formula C with an alkyl halide wherein the alkyl is R in thepresence of sodium hydride to form a compound of the formula III \ -CliD R \N/ R2 I to form a compound of the formula R1 B /\N R2 and reducingthe latter with aluminum chloride and lithium aluminum hydride to formthe corresponding compound of formula I where -p is l and the latter maybe reacted with an acid to form the acid addition salt.

In the latter process, the first reaction is preferably effected in ananhydrous organic solvent such as tetrahydrofuran at reflux of thereaction mixture and the reduction is effected in tetrahydrofuran at 0to 10C.

The indoles of formula lllmay be prepared by the process of Belgium Pat.No. 802,912 by reacting benzyl bromide with a compound of the formulaand reducing the latter with sodium borohydride to obtain a compound ofthe formula wherein R is alkyl of l to 3 carbon atoms and then reducingthe latter with gaseous hydrogen in the presence of a palladium basedcatalyst to form a compound of Formula Ill wherein R is alkyl of l to 3carbon atoms.

A variant of the process permits the preparation of a new intermediatefor the preparation of compounds of formula I wherein X is methoxy, B ismethyl and p is l and the said intermediate is2-methoxy-l0-(a-methylacryloyl)-phenothiazine.

The compounds of formula [V which are not known may be prepared byreacting a compound of the formula with an acid chloride of the formulawherein X and B have the above definition in an organic solvent such astoluene. v i

The novel neuroleptic compositions are comprised of an effective amountof at least one compound of formula l and their non-toxic,pharmaceutically acceptable acid addition salts and a Dharmaceuitcalcarrier.

6 The compositions may be in the form of tablets, AnalysiszcznHmclNasdragees, gelules, granules, suppositories or injectable l'! (1: 7C 70.597H 6.35 7N 8.83 as 6.73 act 7.45 solutions or suspensions prepared inthe usual manner. e c 70.8 I .64 t 8.8

The active ingredients may be incorporated into the usual excipients forpharmaceutical compositionssuch 5 as talc, gum arabic, lactose, amidon,magnesium stearate, cacao butter, aqueous or non-aqueous vehicles,

fats of animal or vegetable origin, paraffinic deriva- EXAMPLE 2 tives,glycols, preservatrons, various wetting agents, (118- 10 y y persants oremulsifiers.

The neuroleptic compositions have a kinetic actionthlaZmyU-pmpy]lplperldm.hydrochlonde which is differed and prolonged andsome of the prod- 17.19 g of 1O-(y-chloropropy Y ucts also possessantihistaminic activity. Depending phenothiazine in 100 ml of methylethyl ketone were upon the specific products, method of administrationadded to a refluxing suspension of 10 g of 3-(4'- and the test used, thebeginning of the effect is more or piperidinyl)-indole and 7.5 g ofsodium iodide in 150 less rapid (generally a few hours) and the durationof ml of methyl ethyl ketone and reflux was continued for the effect ismore or less prolonged (several hour days 24 hours. The mineral residuewas filtered off and the Or even filtrate was concentrated to dryness.The oil residue The oleptic Compositions are useful for the treatwasdissolved in methylene chloride and the solution ment in humans ofchronic psychoses, of schizophenia, WaS Wa With an qu Sodium bicarbonateof delirious or hallucinatory syndromes, of chronic mation and then withwater, was dried and concentrated nia, of manic-depressive psychoses, ofoligophrenia, of to dryness. The residue was dissolved in ether and theCharacter and ehaviour troubles as well as for th solution was filtered.The filtrate was evaporated to treatment of diverse allergicmanifestations. dryness to obtain 17.2 g of 4-(3-indolyl)-l-[y-(2-tri-The novel method of the invention for inducing neu- 25fluoromethyl-10"-phenothiazinyl)-propyl]-piperidine roleptic activity inwarm-blooded animals comprises in the form of an oil. administering towarm-blooded animals an effective The oil was dissolved in ether and thesolution was amount of at least one compound of formula I and itstreated with activated carbon, and filtered. The filtrate non-toxic,pharmaceutically acceptable acid addition was added to hydrochloric acidin ether and the mixsalts. The compounds may be administered orally,rec- 3O ture was filtered. The product was crystallized from a tally orparenterally and the usual effective daily dose is methanol-acetonemixture to obtain 13.4 g of 4-(3'- 0,2 to 5 mg/kg depending upon theproduct of the indolyl)-l-['y-(2"-trifluoromethyl-10"-phen0- method ofadministration. The period between adminthiazinyl)-propyl]-piperidinehydrochloride in the form istration may be a few days up to a few weeks.of white crystals melting at 154C.

Analysis: C H CIF N S Calculated: %C 64.01 %H 5.37 %Cl6.51 %F 10.47 %N7.72 %S 5.89

Found: 64.1 5.5 6.3 10.5 7.4 5.6

In the following examples there are described several EXAMPLE 3preferred embodiments to illustrate the invention. However, it should beunderstood that the invention is4-(5-methoxy-3'-indo1y1)-l-['y-(2"-trifluoromethylnot intended to belimited to the specific embodiments.l0"wphenothiazinyl)-propyl]-piperidine hydrochloride EXAMPLE 1 STEP A:4-(5'-methoxy-3'-indolyl)-piperidine A mixture of 1 1 g of4-(5-methoxy-3-indolyl)- piperidine, 9.5 g of benzyl bromide and 120 mlof ethyl acetate was refluxed for 4 hours and after cooling the 4-( 3'-indo1y1)-1-[y-( 10 -phenothiazinyl)-propyl]- piperidine 'HCl A mixtureof 6.3 g of 10-(7-chloropropyl)-phenothiamixture was. filtered. Therecovered precipitate was zine and 4 g of 3-(4-piperidy1)-indo1e in m1of amyl 55 washed with ethyl acetate and dried under reduced alcohol wasrefluxed for 10 hours and the mixture was 7 pressure to obtain 17.5 g of1-benzyl-4-(5-methoxy-3' evaporated to dryness. The residue waschromatoindolyl)-pyridinium bromide melting at 254C. graphed over silicagel and was eluted with methylene v 3.5 g of sodium borohydride wereadded in small chloride containing 5 percent methanol to obtain 4 g of Iamounts at 40C to a mixture of 17.5 g of 1-benzy1-4-4-(3'-indolyl)-1-['y-(10"-phenothiazinyl)-propyl]- 6'0(5-methoxy-3'-indolyl)-pyridinium bromide in 150 ml piperidine. The saidproduct was dissolved in ether and of methanol abd ml of water and afterstirring the the solution was treated with a solution of hydrochloricmixture at room temperature for 24 hours, m1 of I acid in ether. Theprecipitate formed was crystallized water were added thereto. Theprecipitate formed was from refluxing ether containing 3 percentmethanol recovered by vacuum filtration, was washed with water,

and the mixture was filtered. The precipitate was dried 65 dried andcrystallized from methanol to obtain 13 g of to obtain 3.8 g of4-(3-indoly1)-1-['y-(10"-pheno-1-benzyl-4-(4-methoxy-3-indolyl)-l,2,3,6-tetrahy-'thiazinyl)-propy1]-piperidine hydrochloride in the form dropyridine inthe form of a cream white solid melting of white crystals melting at200C. at 168C.

A mixture of 12.5 g of l-benzyl-4-(5-methoxy-3- ndolyl)-l.2,3,-tetrahydropyridine and 3 g of per- :ent palladized carbon in 300ml of ethanol was heated o 50C while passing hydrogen therein and 1770ml of iydrogen were absorbed in 7 hours. After the reaction vascomplete, the catalyst was filtered off and the filrate was evaporatedto dryness under reduced pres- .ure to obtain 8.3 g of4-(5'-methoxy-3'-indolyl)- )iperidine in the form of white crystalsmelting at 0 70C. lTEP B:4-(5'-methoxy-3'-indolyl)-l-['y-(2"-triluoromethyl- 1 0 -phenothiazinyl)-propyl ]-piperidine lydrochloride A suspension of 8 g of2-trifluoromethyl-l0-(y- :hloropropyl)-phenothiazine, 4.3 g of4-(5'-methoxyl'-indolyl)-piperidine and 3 g of sodium carbonate in 50 mlof amyl alcohol containing a trace of hydroquiione was refluxed forhours and the solvent was hen evaporated. The residue waschromatographed in the form of brown yellow crystals melting at l96l 98Cand slightly soluble in acetonitrile and ben-.

zene.

A mixture of 3.4 g of 4-(2-methyl-6'-methoxy-3'- indolyl)-pyridine and2.65 g of benzyl bromide in ml of ethyl acetate was refluxed for 4 hoursand after cooling the mixture was vacuum filtered. The recovered yellowcrystals were washed with ethyl acetate and dried to obtain 5.7 g of1-benzyl-4-(2-methyl-6'- methoxy-3'-indolyl)-pyridinium bromide in theform of yellow crystals melting at 244246C l g ofl-benzyl-4-(6'-methoxy-2'-methyl-3'bromide in 165 ml of methanol wasadded to 70 ml of water at 40C and afer cooling to 25C, 4 g of sodiumborohydride were added thereto in small amounts while keeping thetemperature below 3035C. The mixture was stirred for 2 hours at roomtemperature and then water was added thereto. The precipitate formed wasrecovered by vacuum filtration, was washed with water and dried underreduced pressure to obtain 15.4 g of 1 -benzyl-4-(2'-methyl-6methoxy-3'-indolyl )-1 ,2,3,6- tetrahydropyridine in the form of orange crystalsmelting at 142-l43C.

24 g of l-benzyl-4-(2'-methyl-6'-methoxy-3'-indolyl)-l,2,3,6-tetrahydropyridine, 4 g of 10 percent palladized carbonand 300 ml of absolute ethanol was heated to 50C and hydrogen wasintroduced. After 12 hours, 2450 ml of hydrogen had been absorbed andthe catalyst was filtered off. Another 3.0 g of 10 percent Ialculated:%C 62.76 %H 5.44 %N 7.32 %C16.18 %F 9.93 %S 5.59 ound: 62.6 5.5 7.00 6.39.9 5.5

alladized carbon was added to the h dro enation EXAMPLE4 p y gfluoromethyl-l0-phenothiazinyl)-propyl]-piperidine .40

mixture of 50 g of 2-methyl-6-methoxy-indole in 230 ml of pyridinecooled to -40C and the mixture was stirred in the dark at roomtemperature for 3 days. The pyridine was evaporated under reducedpressure and the residue was washed with an aqueous sodium hy droxidesolution and the water was evaporated. The pasty product was dissolvedin 500 ml of refluxing methanol and 200 ml of sodium hydroxide followedby 200 ml of water were added thereto with stirring. The mixture wasstirred for 2 hours and allowed to stand overnight after which themethanol was evaporated under reduced pressure. The aqueous phase was extracted with chloroform and the organic phase was dried over sodiumsulfate and evaporated to dryness under reduced pressure to obtain 100 gof raw product. The product was chromatographed over alumina and waseluted with benzene. The benzene was evaporated to obtain 34 g of aproduct in the form of brown crystals which were crystallized fromacetonitrile to obtain 19.5 g of4-(2-methyl-6-methoxy-3-indolyl)-pyridine chamber and the reaction wascontinued for 3 k hours during which 3250 ml of hydrogen were absorbed.The catalyst was filtered off and ethanol was evaporated from thefiltrate under reduced pressue to obtain 16.6 g of4-(2-methyl-6'-methoxy-3-indolyl)-piperidine in the form of whitecrystals melting at 166C. The crystals were soluble in absolute ethanoland slightly soluble in acetonitrile. STEP B:4-(2'-methyl-6'-methoxy-3'-indolyl)-l-[y-(2"-trifluoromethyl-l0-phenothiazinyl)propyl]- piperidine hydrochlorideA mixture of 5 g of 4-(2'-methyl-6-methoxy-3- indolyl)-piperidine, 7.5 gof 2-trifluor0methyl-l0-(ychloropropyl)-phenothiazine, 1.5 g ofpotassium carbonate and 100 ml of amyl alcohol was refluxed for 5 hoursand after the addition of another 1.5 g of potassium carbonate, themixture was refluxed for another 3 hours. 200 ml of methylene chloridewere added thereto and the mixture was chromatographed over silica gel.Elution was with a 1-9 methanol-methylene chloride mixture andevaporation of the solvents gave an oily residue which was taken up inether. Hydrochloric acid in ether was added thereto and the resultingprecipitate was crystallized from ether, vacuum filtered and dried toobtain 4.2 g of 4-(2-methyl-6-methoxy-3-indolyl)-l-[-y-(2trifluoromethyl-l0"-phenothiazinyl]-piperidinehydrochloride in the form of white crystals melting at 200C.

Anulysiszc H N osClF Calculated: 72C 633' 71H 5.66 7rN 7.15 7(S 5.4571Cl6.02 7rF 9.7 Found: 63.0 5.6 7.3 10.0

EXAMPLE 5 4-(3 "indolyl)-l '-[y-(2"-chloro-10"-phenothiazinyl)- propyll-piperidine hydrochloride A mixture of 4 g of 4-(3'-indolyl)piperidine,8 g of 2-chloro-l0-(y-chloropropyl)-phenothiazine, 4.5 g of potassiumcarbonate, 0.7 g of potassium iodide and 200 ml of amyl alcohol wasrefluxed for 20 hours and then 200 ml of a solution of 5 percentpotassium carbonate phenotniazinyl)-propyl]-piperidine in the form of a15 gum. The gum was taken up in ether and hydrochloric acid in ether wasadded thereto to obtain a gum. The latter was crystallized from dioxaneand was treated with refluxing ether containing 2 to 3 percent ofmethaphenothiazinyl)-propyl]-piperidine hydrochloride in the form ofcream crystals melting at 240C.

Analysis: cm m scl molecular weight 510.54

Calculated: %C 65.87 %H 5.73 %N 8.28 %S 6.28 %C|l3.89 Found: 65.5 5.78.3 6.2 14.3

EXAMPLE 6 4-(3-indolyl)-1-[.'y-(2-methoxy-10"-phenothiazinyl)-propyl]-piperidine hydrochloride A mixture of 6.7g of2-methoxy-l0-(y-chloro- 35 propyl)-phenothiazine, 4 g of 4-(3-indolyl)-piperidine, 0.5 g of potassium iodide, 4 g of potassiumcarbonate and 100 ml of amyl alcohol was refluxed for 5 hours and thereaction mixture was then washed with distilled water until the washwaters were neutral. The organic phase was evaporated to dryness and theresidue was chromatographed over silica gel. Elution with a 95'.5methylene chloride-methanol mixture yielded 4 g of 4-(3'-indolyl)-,l-['y-(2-methoxy-l0-phenothiazinyl)- propyl]-piperidine.The said product was dissolved in dioxane and addition of hydrochloricacid in ether formed a precipitate. The product was crystallized fromether containing 2 percent of methanol and then ether to obtain 4.3 g of4-(3indolyl)-l-['y-(2- STEP A: 4-(3'-indolyl)-l-[l"-(2"'-trifluoromethyll"'-phenothiazinyl)-2"-methyl-3"-propionyl]-piperidinehydrochloride 27 g of 2-trifluoromethyl-phenothiazine and 12 g ofa-methylacryloyl chloride in 100 ml of toluene were refluxed for 2 hoursand the mixture was evaporated to dryness. The residue waschromatographed over silica gel and elution with a l--lbenzene-cyclohexane mixture gave 18 g of 2-trifluoromethyl-lO-(a-methylacryloyl)-phenothiazine in the form of white crystals melting at 103C.

A mixture of 6 g of Z-trifluoromethyl-lO-(a-methylacryloyl)-phenothiazine, 8 g of 4-(3'-indolyl)-piperidine and ml oftetrahydrofuran was refluxed wth stirring for 24 hours and afterstopping the heating, the mixture was stirred for 3 days. Theprecipitate was taken up in methylene chloride and the mixture wasfiltered. The filtrate was evaporated to dryness and the residue waschromatographed over silica gel. Elution with I an 85-l5 methylenechloride-ethanol mixture yielded 4-(3'-indolyl)-l-[ l"-(2"-trifluoromethyl-lO'A"-phenothiazinyl)-2"-methyl-3"-propionyl]-piperidine. The said productwas treated with hydrochloric acid in ether to obtain 8.7 g of thecorresponding hydrochloride salt in the form of white crystals meltingat 176C. I STEP B:4-(3-indolyl)-l-[B-methyl-'y-(2"-trifluoromethyl-l0"-phenothiazinyl)-propyl]-piperidinehydrochloride ml of tetrahydrofuran were added under an inert atmosphereand with strong cooling to 2.7 g of lithium aluminum hydride and the 9 gof aluminum chloride were added thereto in small amounts with continuedcooling. .Then, a solution of 8 g of 4-(3-indolyl)-l-[ 1"- (2-trifluoromethyl-l 0' '-phenothiazinyl )-2 '-methyl-3"-propionyl]-piperidine in 50 ml of tetrahydrofuran was added theretodropwise at 0C and then ethylacetate and a saturated sodium sulfatesolution was added over about 2 hours. The mixture was filtered and thefiltrate was washed with ethanol and concentrated to dryness to obtain 6g of 4-(3-indolyl)-l-[B-methyl-'y- (2 -trifluoromethyll0"-phenothiazinyl )-propyl]- piperidine. The said product was taken upin ether to which was added hydrochloric acid in ether. The product waschromatographed over silica gel and was eluted with a 95-5 methylenechloride-ethanol mixture to obtain 2.9 g of the correspondinghydrochloride salt in the form of cream crystals melting at 200C.

Analysis: C H CIF N S Calculated: %c 64.56 %H 5.61 %c1 6.4 %N 7.53 %1=10.2 %s 5.7 Found: 64.1 5.8 6.6 7.5 10.2 5.7

EXAMPLE 8 drochloride in the form of cream crystals melting at Analysis:C H CIN OS 4-(3-indolyl)-l-[y-(2"-methoxy-10"-phenothiazinyl)- B-methylpropyll-piperidine hydrochloridephenothiazinyl)-2"-methyl-3"-propionyl]-piperidine hydrochloride Amixture of 23 g of 2-methoxy-phenothiazine, 21 g of methacryloylchloride and 120 ml of toluene was refluxed for 3 hours and was thencooled and washed with 250 ml of N sodium hydroxide. The organic phasewas decanted and the aqueous phase was washed twice with 50 ml oftoluene. The combined organic phases were wash ed with water. dried overmagnesium sulfate.

. phenothiazinyl)-B-methyl-propyl]piperidine treated with carbon blackand evaporated to dryness to obtain 29.6 g of 2-methoxy-10-(a-methylacryloyl)- phenothiazine melting at 9192C.

A mixture of 6.5 g of 2-methoxy-l0-(a-methyl acryloyl)-phenothiazine, 8g of 4-(3'-indolyl)-piperidine and 30 ml of tetrahydrofuran containing0.15 g of hydroquinone was refluxed for 36 hours and was thenconcentrated to dryness. The residue was taken up in methylene chlorideand the solution was filtered. The filtrate was evaporated to drynessand the residue was chromatographed over silica gel and was eluted withmethylene chloride and then methylene chloride containing 10 percent ofethanol to obtain 9 g of 4-(3'-indolyl)-l-[1"-(2"-methoxy-10"'-phenothiazinyl)-2"-methyl-3"-propionyl]-piperidine in the form of an oil which wastreated with hydrochloride acid in ether to form the correspondinghydrochloride salt melting at STEP B:4-(3-indolyl)-1-[y-(2"-methoxy-10"-phenothiazinyl)-fi-methyl-propyl-l-piperidinehydrochloride 50 ml of tetrahydrofuran were added under an inertatmosphere and with stirring at 30C to 1.7 g of lithium aluminum hydrideand 6 g of aluminum chloride were added in small amounts to the mixtureat 30C. The mixture was stirred for 10 minutes at 10C and then asolution of 6.5 g of 4-(3'-indolyl)-1-[1"-(2"- methoxy- 1 phenothiazinyl)-2 -methyl-3 "-propionyll-piperidine in 50 ml oftetrahydrofuran wasadded thereto. The mixture was stirred for 2 /2 hours at roomtemperature and after cooling to C, 10 ml of ethyl acetate followed by30 ml of water and 200 ml of 2 N hydrochloric acid were added thereto.The aqueous phase was washed with ether, made alkaline and wasextracteclwith chloroform. The organic phase was evaporated to dryness underreduced pressure to obtain 4.5 g of 4-(3-indolyl)-1-[y-(2"-methoxy 10"-in the form of an oil. The oil was taken up in hydrochloric acid inether and the solvent was distilled off. The residue was crystallizedfrom acetonitrile to obtain 2 g of the corresponding hydrochloride, saltmelting at 188C.

Analysis: C H N ClOS; molecular weight 520.15

propyl]-piperidine hydrochloride or 25 mg of 4-(3'-indolyl-l-[y-(2"-methoxy-10-phenothiazinyl)- propylj-piperidinehydrochloride with an excipient of lactose, amidon, talc and magnesiumstearate.

An injectable aqueous suspension was prepared from 10 mg of4-(3-indolyl)-l-['y-(2"-trifluoromethyl-10"-phenothiazinyl)-propyl]-piperidine hydrochloride, 10 mg of benzylalcohol, 8 mg of sodium chloride, 7 mg of emulsifiers and sufficientdistilled water to have 1 ml of the suspension.

PHARMACOLOGICAL DATA The differed and prolonged acting neurolepticproperties and the antihistaminic activity of the compounds of formula Iwere studied in the following tests.

A. Antagonism to stereotypes provoked by apomorphine This test wasconducted on groups of 5 male rats in individual cages with theprocedure of Janssen et a1 [Arzn. Forsch., Vol. 15 (1965), p. 104-117and Vol. 17 (1967), p. 841-854]. Each rat orally received the testcompound and then, at variable times, an intraveinous injection of 1.5mg of apomorphine hydrochloride in the veins of the penis. The times ofinjection were 1 hour, 24 hours, 2 days, 3 days, or 4 days after thetest product administration and the rats were studied during 1 minuteafter 5,10 and 15 minutes after the injection and the sterotypemovements of the jaws spheres were evaluated for their degree ofintensity on a scale for 0 to 3 /Boissier et al, Therapie, Vol 25(1970), p. 939-949/. The ED was determined at the maximum of the effectfor the time considered that is to say the dose reducing the symptoms by50 percent in the treated animals as compared to control animals and theresults are reported in Table l.

B. Antagonism to toxicity provoked by amphetamine This test was effecton groups of 10 male mice grouped in crystallizers with a 20 cm diameterand a 9 cm height closed with a grilled lid. Each mouse orally receiveda determined dose of the test product and at different times a singleintraperitoneal close of dexamphetamine sulfate. The injection waseffected 1 hour, 24 hours or 2,3,4 or 7 days after the administration ofthe test compound and the mortality for each group was determined 24hours after the injection. The ED the dose at which the toxicity ofdexamphetamine sul- Calculated: %c 69.27 %H 6.59 %N 8.08 %c1 6.82 %s6.16 fate was reduced by 50 percent, was determined and i the resultsare reported in Table 1.

TABLE 1 DE in mg/kg 4 Product Apomorphine Ampheta rmmc of SterotypesTox1c1ty Example 1h 24h 2d 3d 4d 1h 24h 2d 3d 4d 7d EXAMPLE 9 Theresults of Table 1 show that the products of the Tablets were preparedfrom 20 mg of 4-(3'-indolyl)-1-['y-(2"-trifluoromethyl-10"-phenothiazinyl)- invention when orallyadministered have important neuroleptic properties appearing more orless rap1dly after the products are administered and the activity has aprolonged duration. i C. Antagonism to stereotypes provoked byamphetamine This test with the product of Example 2 was effected ongroups of 5 rats with the rats individually held'in cages and after therats received intraperitoneally or subcutaneously an aqueous suspensionof the product at a dose of mg/kg, each rat received intraperitoneallyat different times a single injection of 8 mg/kg of dexamphetaminesulfate. The second injections were made 1 hour or 1, 3 or 7 days afterthe first injection and the results were determined by the procedure ofHalliwel et al [Brit. J. PharmacoL, Vol. 23 (1964), p. 330-350]. Thepercentage of protection was determined and the results are reported inTable ll.

Table II shows that the product of Example 2, when injectedintraperitoneally or subcutaneously, has an important antagonisticeffect of prolonged duration against the stereotypes provoked byamphetamine.

D. Antagonism against vomitting provoked by apomorphine This test waseffected on 3 dogs on whom the number of vomits provoked by a singlesubcutaneous injection of 0.1 mg/kg of apomorphine hydrochloride 8 daysbefore this test. Each dog received subcutaneously an in jection of anaqueous suspension of 0.3 mg/kg or 0.8 mg/kg of the product of Example 2and an injection of 0.1 mg/kg of apomorphine hydrochloride 30 minutes, 7days, 14 days, 21 days, 28 days, 35 days and 42 days thereafter. Thepercentage of protection was determined for each time interval and theresults are reported in Table [11.

TABLE III Dose of protection after in mg/kg 30 min. 7d 14d 21d 28d 35d42d TABLE IV Product of Protection After Example I hour 24 hours TableIV shows that the products of the invention possess, when orallyadministered, an important antihistaminic activity which rapidly appearsand is relatively prolonged.

F. Acute toxicity The acute toxicity of the product of Example 2 wasdetermined on groups of 10 mice of the Swiss strain weighing about 20 greceiving increasing doses orally or intraperitoneally of the testproduct. The mortality was determined 72 hours after the productadministration. The LD was about 300 mg/kg intraperitoneally and greaterthan 1,600 mg/kg orally.

Various modifications of the products and methods of the invention maybe made without departing from the spirit or scope thereof and it is tobe understood that the invention is to be limited only as defined in theappended claims.

We claim:

1. A compound selected from the group consisting of a compound of theformula o-z I wherein X is selected from the group consisting ofhydrogen, chlorine, trifluoromethyl, methylthio and methoxy, B isselected from the group consisting of hydrogen and alkyl of l to 3carbon atoms, p is O or 1, R is selected from the group consisting ofhydrogen and alkoxy of l to 3 carbon atoms and R and R are individuallyselected from the group consisting of hydrogen and alkyl of l to 3carbon atoms and their non-toxic, pharmaceutically acceptable acidaddition salts.

2. A compound of claim 1 wherein X is CF p is l and B is selected fromthe group consisting of hydrogen and methyl.

3. A compound of claim 1 wherein X is CF p is l and B and R arehydrogen.

4. A compound of claim 1 which is selected from the group consisting of4-(3'-indolyl)-l [y-( lO-phenothiazinyl)-propyl] piperidine and itsnon-toxic, pharmaceutically acceptable acid addition salts.

5. A compound of claim 1 which is selected from the group consisting of4-(3'-indolyl)-1-[-y-(2"-trifluoromethyl-l '-phenothiazinyl)-propyl]-piperidine and its non-toxic, pharmaceutically acceptabeleacid addition salts.

6. A compound of claim 1 which is selected from the group consisting of4-(5'-methoxy-3'-indolyl)-l-['y- (2 '-trifluoromethyll O -phenothiazinyl)-propyl]- piperidine and its non-toxic, pharmaceutically acceptableacid addition salts.

7. A compound of claim 1 which is selected from the group consisting of4-(2-methyl-6'-methoxy-3'-indolyl)-l-['y-(2"trifluoromethyl-lO"-phenothiazinyl)-propyl]-piperidineand its non-toxic, pharmaceutically acceptable acid addition salts.

8. A compound of claim 1 which is selected from the group consisting of4-(3'-indolyl)-l-[y-(2"chloro-10"- phenothiazinyl)-propyl]-piperidineand its non-toxic, pharmaceutically acceptable acid addition salts.

9. A compound of claim 1 which is selected from the group consisting of4-(3-indolyl)-l-['y-(2"-methoxy- 10"-phenothiazinyl)-propyl]-piperidineand its nontoxic, pharmaceutically acceptable acid addition salts.

10. A compound of claim 1 which is selected from the group consisting of4-(3'-indolyl)-l-['y-(2"- methoxyl 0 '-phenothiazinyl)-B-methyl-propyl]- piperidine and its non-toxic, pharmaceuticallyacceptable acid addition salts.

11. A compound of claim 1 which is selected from the group consisting of4-(3'-indolyl)-l-[y-(2"-trifluoromethyl-l 0 '-phenothiazinyl)-B-methyl-propyl piperidine and its non-toxic, pharmaceuticallyacceptable acid addition salts.

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF A COMPOUND OF THEFORMULA
 2. A compound of claim 1 wherein X is -CF3, p is 1 and B isselected from the group consisting of hydrogen and methyl.
 3. A compoundof claim 1 wherein X is -CF3, p is 1 and B and R1 are hydrogen.
 4. Acompound of claim 1 which is selected from the group consisting of4-(3''-indolyl)-1-( gamma -(10''''-phenothiazinyl)-propyl)-piperidineand its non-toxic, pharmaceutically acceptable acid addition salts.
 5. Acompound of claim 1 which is selected from the group consisting of4-(3''-indolyl)-1-( gamma-(2''''-trifluoromethyl-10''''-phenothiazinyl)-propyl)-piperidine andits non-toxic, pharmaceutically acceptabele acid addition salts.
 6. Acompound of claim 1 which is selected from the group consisting of4-(5''-methoxy-3''-indolyl)-1-( gamma-(2''''-trifluoromethyl-10''''-phenothiazinyl)-propyl)-piperidine andits non-toxic, pharmaceutically acceptable acid addition salts.
 7. Acompound of claim 1 which is selected from the group consisting of4-(2''-methyl-6''-methoxy-3''-indolyl)-1-( gamma-(2''''-trifluoromethyl-10''''-phenothiazinyl)-propyl)-piperidine andits non-toxic, pharmaceutically acceptable acid addition salts.
 8. Acompound of claim 1 which is selected from the group consisting of4-(3''-indolyl)-1-( gamma-(2''''chloro-10''''-phenothiazinyl)-propyl)-piperidine and itsnon-toxic, pharmaceutically acceptable acid addition salts.
 9. Acompound of claim 1 which is selected from the group consisting of4-(3''-indolyl)-1-( gamma-(2''''-methoxy-10''''-phenothiazinyl)-propyl)-piperidine and itsnon-toxic, pharmaceutically acceptable acid addition salts.
 10. Acompound of claim 1 which is selected from the group consisting of4-(3''-indolyl)-1-( gamma -(2''''-methoxy-10''''-phenothiazinyl)- Beta-methyl-propyl)-piperidine and its non-toxic, pharmaceuticallyacceptable acid addition salts.
 11. A compound of claim 1 which isselected from the group consisting of 4-(3''-indolyl)-1-( gamma-(2''''-trifluoromethyl-10''''-phenothiazinyl)- Beta-methyl-propyl)-piperidine and its non-toxic, pharmaceuticallyacceptable acid addition salts.